Despite aggressive efforts to develop new chemotherapeutic treatments for various forms of cancer, current medicines yield now cure rates and undesirable side effects. In the continuing search for more effective anti- cancer agents, marine invertebrates and marine microorganisms have emerged as a promising new resource yielding unusual chemical structures with potent biological activities. The vast diversity, and relatively unexplored nature of these unique sources of chemical diversity suggests they will continue to be an important new source of new drugs. This renewal application describes a National Cooperative Natural Products Discovery Group (NCNPDDG) organized to investigate the chemical diversity found in novel marine microorganisms and selected marine invertebrates. The specific aim of this renewal application is the isolation and characterization of pharmacologically-novel anti-tumor agents. The overall goal of this collaborative effort is to develop new anti- cancer drugs with novel mechanisms of pharmacological action, and with high selectivities toward the most recalcitrant forms of cancer. The research described herein is a continuation of a productive collaboration between the Oncology Drug Discovery Group at Bristol- Myers Squibb (BMS) and marine chemists at the Scripps Institution of Oceanography and The University of Rhode Island. BMS, a leader in the discovery and development of cancer drugs, has a long history of success in this area. A recent modification of the oncology drug discovery effort at BMS has provided access to a highly-novel variety of cancer-relevant screens and predictive biochemical and receptor models. The marine collection contract established at Rhodes University in South Africa. Approximately 500 sponges, ascidians and bryozoans will be collected per year, extracts will be prepared and shipped to SIO for processing and evaluation in the BMS targeted screens. Extracts, and semi-purified fractions, obtained from more than 200 microorganism cultures will be sent to BMS for extensive evaluation in their mechanism based screens. Lead candidates will be selected, and bioassay guided fractionation will be used ti isolate active constituents. Bristol-Myers Squibb will evaluate new compounds in vivo for their chemotherapeutic potential and new agents will be prioritized for development. Twelve promising compounds, and in particular three promising preclinical candidates discovered during the previous grant period, will also be the focus of continued research and development.